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Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; β*(95% CI) = 0.58 (0.44, 0.72); p β*(95% CI) = 0.38 (0.23, 0.54); p r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630

Depression is characterized by altered neurobiological responses to threat and inflammation may be involved in the development and maintenance of symptoms. However, the mechanistic pathways underlying the relationship between the neural underpinnings of threat, inflammation and depressive symptoms remain unknown.Twenty participants with major depressive disorder (MDD) and 17 healthy controls (HCs) completed this study. Peripheral blood mononuclear cells (PBMCs) were collected and stimulated ex vivo with lipopolysaccharide (LPS). We then measured a broad array of secreted proteins and performed principal component analysis to compute an aggregated immune reactivity score. Subjects completed a well-validated emotional face processing task during functional magnetic resonance imaging (fMRI). Amygdala activation was measured during perception of threat for the main contrast of interest: fearhappy face. Participants completed the Mood and Anxiety Symptom Questionnaire (MASQ) and the Perceived Stress Scale (PSS). Correlation analyses between amygdala activation, the aggregate immune score, and symptom were computed across groups. A mediation analysis was also performed across groups to further explore the relationship between these three variables.In line with our hypotheses and with prior work, the MDD group showed greater amygdala activation in response to threat compared to the HC group [tThese data highlight the potential importance of threat circuitry hyperactivation in MDD, consistent with prior reports. We found that higher levels of inflammatory biomarkers were associated with higher amygdala activation, which in turn was associated with anxious arousal. Future research utilizing larger sample sizes are needed to replicate these preliminary results.

Major depressive disorder (MDD) is a leading cause of disability worldwide and less than one-third of patients with MDD achieve stable remission of symptoms, despite currently available treatments. Although MDD represents a serious health problem, a complete understanding of the neurobiological mechanisms underlying this condition continues to be elusive. Accumulating evidence from preclinical and animal studies provides support for the antidepressant potential of modulators of KCNQ voltage-gated potassium (K

Objectives We sought to describe the course and correlates of psychological distress in frontline healthcare workers (FHCWs) during the COVID-19 pandemic in New York City (NYC). Methods A prospective cohort study of FHCWs at the Mount Sinai Hospital was conducted during the initial 2020 surge (T1) and 7 months later (T2). Psychological distress [i.e., positive screen for pandemic-related post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and/or generalized anxiety disorder (GAD)], occupational and personal exposures to COVID-19, coping strategies, and psychosocial characteristics were assessed. Four courses of psychological distress response were identified: no/minimal, remitted, persistent, and new-onset. Multinomial logistic regression and relative importance analyses were conducted to identify factors associated with courses of distress. Results Of 786 FHCWs, 126 (16.0%) FHCWs had persistent distress; 150 (19.1%) remitted distress; 35 (4.5%) new-onset distress; and 475 (60.4%) no/minimal distress. Relative to FHCWs with no/minimal distress, those with persistent distress reported greater relationship worries [19.8% relative variance explained (RVE)], pre-pandemic burnout (18.7% RVE), lower dispositional optimism (9.8% RVE), less emotional support (8.6% RVE), and feeling less valued by hospital leadership (8.4% RVE). Relative to FHCWs with remitted symptoms, those with persistent distress reported less emotional support (29.7% RVE), fewer years in practice (28.3% RVE), and psychiatric history (23.6% RVE). Conclusions One-fifth of FHCWs in our study experienced psychological distress 7 months following the COVID-19 surge in NYC. Pandemic-related worries, pre-pandemic burnout, emotional support, and feeling valued by leaders were linked to persistent distress. Implications for prevention, treatment, and organizational efforts to mitigate distress in FHCWs are discussed. Supplementary Information The online version contains supplementary material available at 10.1007/s00420-022-01832-0.

Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify marked baseline sex differences in the expression of long noncoding RNAs (lncRNAs), a class of regulatory transcripts, in human postmortem brain tissue that are profoundly lost in depression. One such human lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and up-regulated in the prefrontal cortex (PFC) of depressed females only. We found that virally expressing FEDORA selectively either in neurons or in oligodendrocytes of PFC promoted depression-like behavioral abnormalities in female mice only, changes associated with cell type–specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic implications for depressed women and are associated with clinical response to ketamine. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

Promising initial data indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may be beneficial in post-traumatic stress disorder (PTSD). Here, we explore the neural correlates of ketamine-related changes in PTSD symptoms, using a rich battery of functional imaging data (two emotion-processing tasks and one task-free scan), collected from a subset of participants of a randomized clinical trial of repeated-dose intravenous ketamine vs midazolam (total N=21). In a pre-registered analysis, we tested whether changes in an a priori set of imaging measures from a target neural circuit were predictive of improvement in PTSD symptoms, using leave-one-out cross-validated elastic-net regression models (regions of interest in the target circuit consisted of the dorsal and rostral anterior cingulate cortex, ventromedial prefrontal cortex, anterior hippocampus, anterior insula, and amygdala). Improvements in PTSD severity were associated with increased functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala during emotional face-viewing (change score retained in model with minimum predictive error in left-out subjects, standardized regression coefficient [β]=2.90). This effect was stronger in participants who received ketamine compared to midazolam (interaction β=0.86), and persisted following inclusion of concomitant change in depressive symptoms in the analysis model (β=0.69). Improvement following ketamine was also predicted by decreased dorsal anterior cingulate activity during emotional conflict regulation, and increased task-free connectivity between the vmPFC and anterior insula (βs=-2.82, 0.60). Exploratory follow-up analysis via dynamic causal modelling revealed that whilst improvement in PTSD symptoms following either drug was associated with decreased excitatory modulation of amygdala→vmPFC connectivity during emotional face-viewing, increased top-down inhibition of the amygdala by the vmPFC was only observed in participants who improved under ketamine. Individuals with low prefrontal inhibition of amygdala responses to faces at baseline also showed greater improvements following ketamine treatment. These preliminary findings suggest that, specifically under ketamine, improvements in PTSD symptoms are accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat.

Background Clinical trials of intravenous (IV) racemic (R,S)-ketamine (hereafter referred to as IV ketamine) have consistently reported rapid and substantial reductions in overall depressive symptoms compared with saline (inactive placebo) or midazolam (active placebo). The evidence for IV ketamine’s specific effects on suicidal ideation is less clear, however. This study sought to examine whether differential placebo (saline or midazolam) response to overall depressive symptoms vs suicidal ideation may help explain these divergent findings. Methods Data for this participant-level integrative data analysis were drawn from 151 participants across 10 studies, and linear regression was used to examine the relationship between placebo response for suicidal ideation vs other depressive symptoms indexed from standard rating scales—specifically, depressed mood, anhedonia, anxiety, and guilt—over time. Results For participants receiving saline placebo (n = 46), greater placebo response was observed for suicidal ideation compared with other symptoms indexed from standard depression rating scales, except for anxiety. For those receiving midazolam placebo (n = 105), greater placebo response was observed for suicidal ideation compared with depressed mood or anhedonia, and no significant differences were observed when comparing suicidal ideation with anxiety or guilt. Conclusions Taken together, the results provide preliminary evidence of a differential placebo response for suicidal ideation vs other depressive symptoms, while anxiety and suicidal ideation appear to produce similar placebo response profiles. These findings may help explain the more modest findings in clinical IV ketamine trials for suicidal ideation than overall depression.

BackgroundThe sense of agency, or the belief in action causality, is an elusive construct that impacts day-to-day experience and decision-making. Despite its relevance in a range of neuropsychiatric disorders, it is widely under-studied and remains difficult to measure objectively in patient populations. We developed and tested a novel cognitive measure of valence-modulated agency perception in an in-person and online cohort.MethodsThe in-person cohort consisted of 52 healthy control subjects and 20 subjects with depression and anxiety disorders (DA), including major depressive disorder and generalized anxiety disorder. The online sample consisted of 254 participants. The task consisted of an effort task for monetary rewards with computerized visual feedback interference and trial-by-trial ratings of self versus other agency.ResultsAll subjects across both cohorts demonstrated higher self-agency after receiving positive-win feedback, compared to negative-loss feedback when the level of computer inference was kept constant. Patients with DA showed reduced positive valence-dependent agency compared to healthy controls. Finally, in both cohorts, lower self-agency following negative-loss feedback was associated with worse anhedonia symptoms.ConclusionTogether this work suggests how positive and negative environmental information impacts the sense of self-agency in healthy subjects, and how it is perturbed in patients with depression and anxiety.

Objectives: On a background of the rapidly expanding clinical use of ketamine and esketamine for treatment of depression and other conditions, we examined safety monitoring, seeking to identify knowledge gaps relevant to clinical practice.Methods: An international group of psychiatrists discussed the issue of safety of ketamine and esketamine and came to a consensus on key safety gaps.Results: There is no standard safety monitoring for off-label generic ketamine. For intranasal esketamine, each jurisdiction providing regulatory approval may specify monitoring. Treatment is often provided beyond the period for which safety has been demonstrated, with no agreed framework for monitoring of longer term side effects for either generic ketamine or intranasal esketamine.Limitations: The KSET has established face and content validity, however it has not been validated against other measures of safety.Conclusions: We recommend the Ketamine Side Effect Tool (KSET) as a comprehensive safety monitoring tool for acute and longer term side effects.

Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.

Ketamine is an N-methyl-D-aspartate receptor antagonist with rapid antidepressant effects. Studies suggest that inhibition of nitric oxide synthesis plays a role in the mechanism of action of ketamine. This randomized, placebo-controlled study investigated whether co-administration of sodium nitroprusside, a nitric oxide donor, compared to placebo, would attenuate the antidepressant and dissociative effects of ketamine. Sixteen ketamine responders were randomized to a double-blind infusion of ketamine co-administered with placebo or sodium nitroprusside. Our findings show no difference between the two conditions suggesting that the nitric oxide pathway may not play a primary role in ketamine’s antidepressant or dissociative effects. The study is registered at clinicaltrials.gov (NCT03102736).

Anhedonia - the reduced ability to experience or respond to pleasure - is an important symptom domain for many psychiatric disorders. It is particularly relevant to depression and other mood disorders and it is a diagnostic criterion of a major depressive episode. Developing safe and effective pharmacological interventions for anhedonia is a critical public health need. The current chapter will review the state of the field with respect to both the efficacy of currently available pharmacotherapies for anhedonia and the recent clinical research focusing on new brain targets, including the kappa-opioid receptor and the KCNQ2/3 receptors. The evidence for anti-anhedonic effects of ketamine and psychedelic agents will be reviewed, as well.

BackgroundKetamine’s potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor–dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states.MethodsResting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined.ResultsA reduction in Montgomery–Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P ConclusionsThese preliminary results suggest that the Hb might be involved in ketamine’s antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.

Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies, impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in vivo molecular mechanisms of brain IR until recently have proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared with age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM+ exosomes in subjects with MDD as compared with age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM+ exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM+ exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM+ exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.

(1) Background: This study examined the prevalence and correlates of factors associated with self-reported mental health service use in a longitudinal cohort of frontline health care workers (FHCWs) providing care to patients with COVID-19 throughout 2020. (2) Methods: The study comprised a two-wave survey (n = 780) administered in April–May 2020 (T1) and November 2020–January 2021 (T2) to faculty, staff, and trainees in a large urban medical center. Factors associated with initiation, cessation, or continuation of mental health care over time were examined. (3) Results: A total of 19.1% of FHCWs endorsed currently utilizing mental health services, with 11.4% continuing, 4.2% initiating, and 3.5% ceasing services between T1 and T2. Predisposing and need-related factors, most notably a history of a mental health diagnosis and distress related to systemic racism, predicted service initiation and continuation. Among FHCWs with a prior mental health history, those with greater perceived resilience were less likely to initiate treatment at T2. Descriptive data highlighted the importance of services around basic and safety needs (e.g., reliable access to personal protective equipment) relative to mental health support in the acute phase of the pandemic. (4) Conclusions: Results may be helpful in identifying FHCWs who may benefit from mental health services.

To evaluate the direct and interacting effects of personal and systemic factors that contribute to psychological distress among frontline healthcare workers (FHCWs) during the COVID-19 pandemic.Data were collected using a hospital-wide, cross-sectional survey. A multivariable binary logistic regression and relative importance analysis was conducted to identify factors associated with screening positive for C19-distress.A total of 1005 (39.0%, 95%CI - 37.1-40.9%) out of 2579 FHCWs met the prespecified cutoff values for significant symptoms of C19-distress. Fewer sleep hours and lower perceptions of leadership support explained the majority of variance (19.4% relative variance explained [RVE]) in C19-distress, followed by team camaraderie (6.4% RVE), physical exercise (4.9% RVE), and engagement in hobbies (3.2% RVE).These results underscore the importance of restorative behaviors as potential targets to help decrease distress and promote resilience in FHCWs.

Increased levels of peripheral cytokines have been previously associated with depression in preclinical and clinical research. Although the precise nature of peripheral immune dysfunction in depression remains unclear, evidence from animal studies points towards a dysregulated response of peripheral leukocytes as a risk factor for stress susceptibility. This study examined dynamic release of inflammatory blood factors from peripheral blood mononuclear cells (PBMC) in depressed patients and associations with neural and behavioral measures of reward processing. Thirty unmedicated patients meeting criteria for unipolar depressive disorder and 21 healthy control volunteers were enrolled. PBMCs were isolated from whole blood and stimulated ex vivo with lipopolysaccharide (LPS). Olink multiplex assay was used to analyze a large panel of inflammatory proteins. Participants completed functional magnetic resonance imaging with an incentive flanker task to probe neural responses to reward anticipation, as well as clinical measures of anhedonia and pleasure including the Temporal Experience of Pleasure Scale (TEPS) and the Snaith-Hamilton Pleasure Scale (SHAPS). LPS stimulation revealed larger increases in immune factors in depressed compared to healthy subjects using an aggregate immune score (t49 = 2.83, p = 0.007). Higher peripheral immune score was associated with reduced neural responses to reward anticipation within the ventral striatum (VS) (r = −0.39, p = 0.01), and with reduced anticipation of pleasure as measured with the TEPS anticipatory sub-score (r = −0.318, p = 0.023). Our study provides new evidence suggesting that dynamic hyper-reactivity of peripheral leukocytes in depressed patients is associated with blunted activation of the brain reward system and lower subjective anticipation of pleasure.

Anxiety disorders are the most prevalent psychiatric disorders and a leading cause of disability. While there continues to be expansive research in posttraumatic stress disorder (PTSD), depression and schizophrenia, there is a relative dearth of novel medications under investigation for anxiety disorders. This review's first aim is to summarize current pharmacological treatments (both approved and off-label) for panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and specific phobias (SP), including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), azapirones (e.g., buspirone), mixed antidepressants (e.g., mirtazapine), antipsychotics, antihistamines (e.g., hydroxyzine), alpha- and beta-adrenergic medications (e.g., propranolol, clonidine), and GABAergic medications (benzodiazepines, pregabalin, and gabapentin). Posttraumatic stress disorder and obsessive-compulsive disorder are excluded from this review. Second, we will review novel pharmacotherapeutic agents under investigation for the treatment of anxiety disorders in adults. The pathways and neurotransmitters reviewed include serotonergic agents, glutamate modulators, GABAergic medications, neuropeptides, neurosteroids, alpha- and beta-adrenergic agents, cannabinoids, and natural remedies. The outcome of the review reveals a lack of randomized double-blind placebo- controlled trials for anxiety disorders and few studies comparing novel treatments to existing anxiolytic agents. Although there are some recent randomized controlled trials for novel agents including neuropeptides, glutamatergic agents (such as ketamine and d-cycloserine), and cannabinoids (including cannabidiol) primarily in GAD or SAD, these trials have largely been negative, with only some promise for kava and PH94B (an inhaled neurosteroid). Overall, the progression of current and future psychopharmacology research in anxiety disorders suggests that there needs to be further expansion in research of these novel pathways and larger-scale studies of promising agents with positive results from smaller trials.

Synaptic plasticity and brain-derived neurotrophic factor (BDNF) signalling are proposed to play key roles in antidepressant drug action. Ketamine, an N-methyl-D-aspartate receptor antagonist and putative antidepressant, may increase synaptic plasticity in prefrontal cortex through higher expression of BDNF. Furthermore, ketamine was shown to change resting-state functional connectivity (RSFC) of dorsomedial prefrontal cortex (dmPFC).In a randomised, placebo-controlled study, we investigated acutely (100 min) and at 24 h following subanesthetic ketamine infusion which dmPFC seeded RSFC changes are most strongly associated with plasma BDNF level changes in 53 healthy participants (21 females, age: 24.4 ± 2.9 years) using 7 T-fMRI.We observed higher relative levels of BDNF 2 h and 24 h after ketamine compared to placebo. Whole-brain regression revealed that the change in BDNF after 24 h was associated with RSFC decreases from dmPFC to posterior cingulate cortex and ventromedial PFC at 24 h and exploratively also at the 100 min measurement point. Follow-up analyses revealed that RSFC reductions following ketamine were restricted to subjects showing increased BDNF levels at 24 h.Our findings indicate BDNF level dynamics following ketamine are related to acute and 24 h RSFC changes. Particularly when BDNF increases are observed after ketamine infusion, a disconnection from dmPFC after 24 h is seen and may reflect synaptic plasticity effects.

Stress-related neuropsychiatric disorders, such as major depressive disorder and posttraumatic stress disorder, exact enormous socioeconomic and individual consequences. Resilience, the process of adaptation in the face of adversity, is an important concept that is enabling the field to understand individual differences in stress responses, with the hope of harnessing this information for the development of novel therapeutics that mimic the body's natural resilience mechanisms. This review provides an update on the current state of research of the neurobiological mechanisms of stress resilience. We focus on physiological and transcriptional adaptations of specific brain circuits, the role of cellular and humoral factors of the immune system, the gut microbiota, and changes at the interface between the brain and the periphery, the blood-brain barrier. We propose viewing resilience as a process that requires the integration of multiple central and peripheral systems and that elucidating the underlying neurobiological mechanisms will ultimately lead to novel therapeutic options.

Clinical outcome assessments may not fully capture patients’ perspectives of treatment benefit or tolerability. Incorporating individual exit interviews might enhance the description of the patient experience of drug effects. The objective of this study was to evaluate the patient treatment experience in a clinical trial of treatment-resistant depression utilizing exit interview methodology. Individual patient interviews were conducted with subjects exiting two phase II clinical trials involving investigational agents for treatment-resistant depression. Interviews included standardized questions about patients’ perceptions of health changes and interest in continued use of the investigational agent. Constant comparative analysis of blinded data was used to identify, code, and categorize the data followed by a subsequent analysis of unblinded data to evaluate any potential treatment differences. Ninety subjects completed exit interviews across the two trials. Most subjects (90%, Trial 2001; 74%, Trial 2002) reported at least one health change. Most subjects rated these changes to be at least moderately important, with most being rated “very important” to “extremely important.” After unblinding, participants receiving active therapy alone reported most of the positive health changes (80% of overall positive changes in Trial 2001, 89% in Trial 2002), whereas patients taking placebo alone reported the majority of negative health changes (57% in Trial 2002). Positive changes included not only anticipated changes in mood but also potential cognitive benefits such as mental alertness, improved sleep, and better concentration. Standardized interview data provided direct patient insight into the treatment experience from the patient perspective. Data from these interviews assisted in phase III endpoint selection by providing data on relevant concepts in the target treatment-resistant depression population receiving a new treatment, thus enabling the selection of tools to capture noted treatment effects and, by eliminating irrelevant constructs or measures, thereby reducing data “noise.” ClinicalTrials.gov NCT01640080; NCT01627782.

Highlights •Depression is a common problem and is associated with increased mortality and reduced quality of life in patients with CVD. •Depression complicates the optimal management of CVD by worsening cardiovascular risk factors and decreasing adherence to healthy lifestyles and evidence-based medical therapies. •Standardized screening pathways for depression in patients with CVD offer the potential for early identification and optimal management of depression to improve health outcomes.

The goal of this study was to infer the effectiveness of midazolam as a comparator in preserving the blind in ketamine studies for mood disorders through patient-level analyses of efficacy trial outcomes. In this integrative data analysis (k = 9, N = 367 patients with mood disorders), clinical outcomes were compared across four groups: ketamine (midazolam-controlled), ketamine (saline-controlled), midazolam, and saline. Ketamine doses ranged from 0.5 to 0.54 mg/kg and midazolam doses ranged from 0.02 to 0.045 mg/kg. The baseline-to-Day 1 effect size was d = 0.7 (95% CI: 0.4–0.9) for ketamine (midazolam) versus midazolam and d = 1.8 (95% CI: 1.4–2.2) for ketamine (saline) versus saline. The effect of ketamine relative to control was larger in saline-controlled studies than in midazolam-controlled studies (t(276) = 2.32, p = 0.02). This was driven by a comparatively larger effect under midazolam than saline (t(111) = 5.40, p

BACKGROUND The COVID-19 pandemic has resulted in a high degree of psychological distress among health care workers (HCWs). There is a need to characterize which HCWs are at an increased risk of developing psychological effects from the pandemic. Given the differences in the response of individuals to stress, an analysis of both the perceived and physiological consequences of stressors can provide a comprehensive evaluation of its impact. OBJECTIVE This study aimed to determine characteristics associated with longitudinal perceived stress in HCWs and to assess whether changes in heart rate variability (HRV), a marker of autonomic nervous system function, are associated with features protective against longitudinal stress. METHODS HCWs across 7 hospitals in New York City, NY, were prospectively followed in an ongoing observational digital study using the custom Warrior Watch Study app. Participants wore an Apple Watch for the duration of the study to measure HRV throughout the follow-up period. Surveys measuring perceived stress, resilience, emotional support, quality of life, and optimism were collected at baseline and longitudinally. RESULTS A total of 361 participants (mean age 36.8, SD 10.1 years; female: n=246, 69.3%) were enrolled. Multivariate analysis found New York City’s COVID-19 case count to be associated with increased longitudinal stress (P=.008). Baseline emotional support, quality of life, and resilience were associated with decreased longitudinal stress (P<.001). A significant reduction in stress during the 4-week period after COVID-19 diagnosis was observed in the highest tertial of emotional support (P=.03) and resilience (P=.006). Participants in the highest tertial of baseline emotional support and resilience had a significantly different circadian pattern of longitudinally collected HRV compared to subjects in the low or medium tertial. CONCLUSIONS High resilience, emotional support, and quality of life place HCWs at reduced risk of longitudinal perceived stress and have a distinct physiological stress profile. Our findings support the use of these characteristics to identify HCWs at risk of the psychological and physiological stress effects of the pandemic.